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Introduction & Purpose: Breast density, the relative amount of fibroglandular versus fatty tissue in the breast, is one of the strongest breast cancer risk factors. Understanding genetic factors associated with breast density may help clarify mechanisms by which breast density increases breast cancer risk. To date, 46 genetic loci have been associated with breast density, however, these studies have been performed among predominantly European ancestry populations. This study sought to identify genetic factors associated with breast density among women of African ancestry. Methods: We utilized a cohort of women aged 40-85 years who underwent screening mammography at the Hospital of the University of Pennsylvania from 2010-2014. The cohort was linked to the Penn Medicine BioBank (PMBB), a repository of DNA samples from consenting patients. We conducted a genome-wide association study (GWAS) of breast density among women with available genotypes who either self-reported their race as Black/African American, or had an African ancestry genotype (N = 1,323). For each mammogram, the publicly available “LIBRA” software (v1.0.4) was used to quantify dense area and area percent density (dense area divided by breast area) from raw (i.e., FOR PROCESSING) full-field digital mammograms (Selenia Dimensions, Hologic Inc.). Women completed a breast cancer risk factor questionnaire at the time of mammography and BMI was obtained from electronic health records. We tested for associations of dense area and area percent density with ~8.5M common variants, adjusting for age, BMI, menopausal status, and two principle components of ancestry as covariates. Results: We identified three novel loci associated with dense area at genome wide significance (p < 5e-08), including KCNA3 (rs61803939, p =3.40e-08, beta=3.26, SE=0.59) and two nearby loci on chromosome 19, ZNF486 (rs6511094, p =1.41e-08, beta=2.44, SE=0.43) and LOC100129265 (rs1428621382 p = 5.13E-08, beta=2.40, SE=0.44). Our results also replicated three previously reported signals near genes TET3 associated with dense area, TNS1 and SMIM25 associated with area percent density at nominally significant p < 1e-06. Conclusions: To our knowledge, this is the first breast density GWAS in women of African ancestry. Although the study had a small sample size, the analyses replicated associations of three known genes and also identified three novel breast density loci. Notably, variant rs61803939 mapping to KCNA3 gene is present in samples of African ancestry at a higher frequency (MAF=0.14) than in samples of European ancestry (MAF=0.09). Additionally, this variant also has a high oncogenecity score (Phred Score=21.9) and is estimated as likely driver of cancer. Further investigation of the role of variants in KCNA3 in breast density and in influencing the breast cancer risk are warranted, as are larger GWAS evaluating genetic variants for breast density among African ancestry populations. Citation Format: Shefali Verma, Lindsay Guare, Aimilia Gastounioti, Sarah Ehsan, Emily F. Conant, Marylyn Ritchie, Despina Kontos, Anne Marie McCarthy. Genome wide association study of breast density among women of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5871.